Parasitic worms of the family Trematoda, including the genus Schistosoma (e.g., S. mansoni, S. haematobium, S. japonicum, and the like) and Echinostoma are the causative agents of mammalian disease. In particular, Schistosoma worms are responsible for human schistosomiasis. Worldwide approximately 200 million people are actively infected, with an additional 500-600 million at risk. A large number (more than 20 million) of those infected show severe chronic illness, resulting from damage to various organ systems including the liver, bladder, heart, lungs, spleen, and intestine.
Schistosoma are a blood fluke which inhabit the vasculature serving the liver, bladder, intestine and spleen of a human host. A mating pair of the worms live from several to more than 30 years wherein they can continuously shed from 300 to more than 3000 eggs per day. The adult worms do not reproduce themselves within the human body. The eggs of these worms leave the body of an infected individual through the urine and feces. If they reach water, they hatch into a first larval stage, or miracidia. The miracidia, which are completely formed within the eggs, resemble ciliates. They must reach their freshwater snail host within a few hours to survive. If they reach their host, they develop into sporocysts. The sporocysts divide asexually to give rise to daughter sporocysts, and the daughter sporocysts in turn give rise to cercariae, a tadpole-like larval stage. A single infected snail can release 100,000 cercariae during its lifetime of several months. The cercariae of Schistosoma burrow into human skin, ultimately reaching the bloodstream where they are swept into the lungs. Subsequently, the cercariae mature and pair during their migration to the veins which supply the upper intestine, the lower intestine, the liver, or the bladder, depending on the species of Schistosoma involved.
Pathogenesis of schistosomiasis is not due to the presence, nor the blood feeding of the adult worms, but, rather, results from an immune reaction to the large number of eggs produced and released by the female worms. A large percentage of these eggs become trapped in various tissues (liver, spleen, etc.) with resultant inflammation and granuloma formation. The remainder of the eggs pass through intestinal or bladder tissues and are released into the environment, which is essential for continuation of the schistosome life cycle and disease transmission.
Currently there are only three drugs used in chemotherapy of schistosomiasis. These include metrifonate (Trichlorfon; (2,2,2-trichloro-1-hydroxyethyl)-phosphonic acid dimethyl ester), oxamniquine (1,2,3,4-tetrahydro-2-[[(1-methylethyl)amino]methyl]-7-nitro-6-quinolinemethanol), and praziquantel (2-(cyclohexylcarbonyl)-1,2,3,6,7,-11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one). All three drugs are effective to varying degrees and can eliminate adult worms from the human host. Praziquantel is the current drug of choice and has been used successfully worldwide against all three species of schistosomes. It has been suggested that praziquantel functions by causing exposure of normally hidden worm surface proteins and glycoproteins to the host immune system. Some or all of these surface xe2x80x9cantigensxe2x80x9d may not be essential for worm survival, and a decrease in their production and/or use by schistosomes could be driven by praziquantel treatment. If so, resistance to praziquantel would be expected to increase in the future driven by the repeated dosing of praziquantel practiced in some endemic areas. In fact, there is increasing evidence of emergence of praziquantel resistant strains of S. mansoni in certain regions of the world. Such reports are particularly disturbing because metrifonate is only effective against S. haematobium infections, and S. mansoni resistance to oxamniquine has previously been reported.
Chemotherapy with each of these drugs only seeks to eliminate the adult worms in an infected individual. Removal of the adult worm does not confer protection against reinfection. Since reinfection occurs frequently in endemic areas, praziquantel and the other anti-schistosomal agents must be used repeatedly to control the disease, thereby increasing the pressure for continued emergence of drug resistance and increasing the cost of treatment.
In light of the increasing reports of drug resistance, new avenues of chemotherapeutic control of schistosomiasis are needed. At present, there is little work being done to identify new agents with antischistosomal properties, and most work has yet to progress past initial testing in a mouse model. The bulk of the current research effort to control human schistosomiasis is devoted to construction of an anti-schistosomal vaccine. Development of an effective vaccine against schistosomiasis would be of enormous benefit because of its potential to prevent infection. However, no vaccine affording such protection has yet been achieved despite nearly two decades of work. Further, there are major economic and logistical problems to effectively deploying a modern vaccine in the developing countries where schistosomiasis is endemic.
Surprisingly, the present invention provides methods and compositions for the inhibition of egg production by adult Trematoda worms. In particular, methods for the inhibition of egg production by Schistosoma, Echinostoma and Fasciola worms. The inhibition of egg production, in addition to reducing or eliminating pathology related to infection of the host, also reduces (or possibly eliminates) the release of Trematoda eggs into the environment to continue the worm life cycle. By reducing the number of eggs released into the environment the method of the present invention provides a means to effectively reduce the rate of reinfection of the mammalian host.
The purpose of the invention described herein is to provide a method for inhibiting the production of eggs from parasitic trematode worms by administering an agent which transiently inhibits the function of calcium channels. The methods can be used to treat, for example, schistosomiasis, and to inhibit both the pathology and transmission of schistosomiasis in humans.
Many of the agents effective in the methods of the present invention comprise compounds that are used currently in the treatment of hypertension, arrhythmias, angina and other cardiovascular diseases. Generally, all of the agents useful in the methods of the present invention should be capable of transiently blocking the influx of extracellular calcium through calcium channels in the plasma membrane of a wide variety of cells. In particular, agents effective in the methods of the present invention comprise molecules which comprise dihydropyridine, phenylalkylamine, benzothiazepine, diphenylbutylpiperdine or flunarizine/cinnarizine compounds, and the like. Of particular interest are the commonly prescribed calcium channel blockers verapamil, nifedipine, diltiazem, and nicardipine.